1. Field of the Invention
The present invention relates generally to the fields of cancer biology and drug delivery and, more specifically, to peptides that selectively home to angiogenic vasculature, particularly in a tumor, to compositions comprising an agent such as a therapeutic agent conjugated to such angiogenic vasculature homing molecules, and to methods of using such molecules to target an agent to angiogenic vasculature.
2. Background Information
Continuous developments over the past quarter century have resulted in substantial improvements in the ability of a physician to diagnose a cancer in a patient. For example, antibody based assays such as that for prostate specific antigen now allow early diagnosis of cancers such as prostate cancer. More recently, methods of genetic screening are becoming available to identify persons that may be particularly susceptible to developing a cancer. Genetic screening methods are based on the identification of one or more mutations in a gene that correlates with the development of a cancer. For example, the identification of genes such as BRCAl and BRCA2 allowed the further identification of mutations in these genes that, in some cases, can correlate with susceptibility to developing breast cancer.
Unfortunately, methods for treating cancer have not kept pace with those for diagnosing the disease. Thus, while the death rate from various cancers has decreased due to the ability of a physician to detect the disease at an earlier stage, the ability to treat patients presenting with more advanced disease has progressed only minimally.
A major hurdle to advances in treating cancer is the relative lack of agents that can selectively target the cancer, while sparing normal tissue. For example, radiation therapy and surgery, which generally are localized treatments, can cause substantial damage to normal tissue in the treatment field, resulting in scarring and, in severe cases, loss of function of the normal tissue. Chemotherapy, in comparison, which generally is administered systemically, can cause substantial damage to organs such as bone marrow, mucosae, skin and the small intestine, which undergo rapid cell turnover and continuous cell division. As a result, undesirable side effects such as nausea, loss of hair and drop in blood cell count occur as a result of systemically treating a cancer patient with chemotherapeutic agents. Such undesirable side effects often limit the amount of a treatment that can be administered. Thus, cancer remains a leading cause of patient morbidity and death.
Efforts have been made to increase the target specificity of various drugs. For example, where a unique cell surface marker is expressed by a population of cells making up a tumor, an antibody can be raised against the unique marker and a drug can be linked to the antibody. Upon administration of the drug/antibody complex to the patient, the binding of the antibody to the marker results in the delivery of a relatively high concentration of the drug to the tumor. Similar methods can be used where a particular cancer cell or the supporting cell or matrix expresses a unique cell surface receptor or a ligand for a particular receptor. In these cases, the drug can be linked to the specific ligand or to the receptor, respectively, thus providing a means to deliver a relatively high concentration of the drug to the tumor.
Tumors are characterized, in part, by a relatively high level of active angiogenesis, resulting in the continual formation of new blood vessels to support the growing tumor. Such angiogenic blood vessels are distinguishable from mature vasculature. One of the distinguishing features of angiogenic vasculature is that unique endothelial cell surface markers are expressed. Thus, the blood vessels in a tumor provide a potential target for directing a chemotherapeutic agent to the tumor, thereby reducing the likelihood that the agent will kill sensitive normal tissues.
Although antibody-based therapies have been effective at treating certain types of cancer, antibody-based therapies also have limitations, mostly due to poor tissue penetration and unwanted immune response. Therefore, the identification of small molecules such as peptides capable of targeting cells within tumor vasculature or stroma can be useful in alleviating many of the problems associated with antibody-based targeting strategies.
While linking a drug to a molecule that homes to a tumor can provide significant advantages for treatment over the use of a drug, alone, use of this method is severely limited by the scarcity of useful cell surface markers expressed in a tumor. Thus, a need exists to identify molecules that can selectively home to a tumor, particularly to the vasculature supporting the tumor. The present invention satisfies this need and provides related advantages as well.
The present invention provides angiogenic vasculature homing molecules that bind to NG2/HM proteoglycan. Angiogenic vasculature homing molecules of the invention include, for example, a peptide comprising the amino acid sequence TAASGVRSMH (SEQ ID NO:1) or LTLRWVGLMS (SEQ ID NO:2). The invention also provides conjugates comprising an angiogenic vasculature homing molecule linked to a moiety such as a drug, a cytotoxic agent, a chemotherapeutic agent, or a detectable agent.
The invention additionally provides a method of targeting angiogenic vasculature in a tumor in vivo. The method includes the steps of contacting the angiogenic vasculature with an angiogenic vasculature homing molecule that selectively homes to a NG2/HM proteoglycan, wherein the angiogenic vasculature homing molecule is not an antibody. The method can be used to target a drug, a cytotoxic agent, or a chemotherapeutic agent to angiogenic vasculature, or can be used to target a detectable agent for imaging a tumor, tissue or organ associated with angiogenic vasculature.
The invention further provides a method of inhibiting angiogenesis in a tumor of a subject. The method includes the steps of administering to the subject a conjugate comprising a moiety linked to an angiogenic vasculature homing molecule that selectively binds a NG2/HM proteoglycan, wherein the angiogenic vasculature homing molecule is not an antibody. The method can be used to inhibit angiogenesis by targeting an angiogenic vasculature homing molecule linked to a therapeutic moiety to the angiogenic vasculature of a tumor.